Many proliferative skin diseases (psoriasis, vitiligo, eczema, mycosis fungoides, etc), cancerous conditions (T cell lymphomas), and autoimmune disorders are being treated by the combined utilization of photosensitizing chemicals [applied topically or taken orally] plus ultraviolet light. Terms such as photosensitization, photochemotherapy, photopheresis and PUVA (psoralens ultra violet A radiation) are commonly used to refer to special applications of this method. Clinically useful behavior has been found in such chemical families as heme-derived products, porphyrins, phthalocyanins, and psoralens. The oldest and most established phototherapeutics are the psoralens or linear furocoumarins in which three major commercial pharmaceuticals dominate: 8-methoxypsoralen (methoxsalen or 8-MOP); 4,5',8-trimethylpsoralen (trioxsalen or TMP), and 5-methoxypsoralen (5-MOP).
The widely accepted mechanism of action for psoralens is penetration of the target cell's membrane, intercalation into nuclear DNA, and photo-induced bis 2+2 cycloaddition crosslinking of the double helix. Structural and mechanism studies have shown that the 3,4-double bond and the 4',5'-double bond in psoralen (Formula 0 below) form cyclobutane adducts with the double bonds in the pyrimidine bases of DNA. This renders the DNA unable to uncoil and serve as a template for new gene expression. Thus, the target cell is rendered non-viable (J. E. Hearst, Chemical Research in Toxicology, 2, 69, 1989; T. F. Anderson and J. J. Vorhees, Ann. Rev. Pharmacol. Toxicol., 10, 177, 1982).
The basic structure of psoralen with the ring numbering structure used herein, is as depicted in Formula O below. ##STR1##
A severe limitation to the acceptance of psoralen-based photochemotherapy is the understanding that the natural cellular level repair processes of bi-functional DNA-crosslinks are highly error-prone. Errors in cellular repair processes of true crosslinks translate to mutagenic/carcinogenic events and, in the clinical use of psoralens, represent a significant post-treatment risk of cancer induction. It is known in the art that bent, nonlinear furocoumarins (known as angelicins), which are by their structure limited to the photogeneration of only non-crosslinked mono-adducts, are far less mutagenic/carcinogenic (F. Baccichetti et al., U.S. Pat. No. 4,312,883; R. S. Cole, "Repair of DNA Containing Interstrand Crosslinks in E Coli," Proc. Nat. Acad Sci. USA, 70, 1064, 1973).
An alternative mechanism is available by which psoralens manifest phototoxicity to a cell. A 22,000 Da protein present in psoralen-sensitive cells has been found to be a specific binding site for photo-activated psoralens. The binding of psoralens to this receptor followed by UVA light activation prevents the binding of epidermal growth factor (EGF), an important cellular messenger for growth and differentiation. Thus, the therapeutic photobiology of psoralens can be explained by a non-DNA target for their molecular activity (N. D. Heindel, J. Van Dongen, B. S. Sachais, J. H. Phillips, M. A. Gallo, and J. D. Laskin, J. Pharm. Sci., 80, 686, 1991).